Process for preparing 4-hydroxy-3-keto-5alpha-steroids and ethers of 3-hydroxy-delta3-5alpha-steroids intermediates therein



United States Patent 3 264 329 PROCESS FOR PREPXRlhiG 4-HYDROXY-3-KETO- Set-STEROIDS AND ETHERS 0F 3-HYDROXY-A SIX-STEROIDS INTERMEDIATE THEREIN Alberto Ercoli and Rinaldo Gardi, Milan, Italy, assignors to Francesco Vismara S.-p.A., Casatenovo (Como), Italy No Drawing. Filed Nov. 26, 1962, Ser. No. 240,143

Claims priority, application Italy, Nov. 27, 1961, 21,283/ 61 8 Claims. (Cl. 260-3914) The present invention relates to new steroid compounds and is more particularly concerned with the new ethers of 3-hydroxy-A -a-steroids and to a process for their preparation.

It is known to prepare enolethers of 3-keto-5oi-steroids from the enolethers of the corresponding A -3-ketones (ethers of 3-hydroxy-3,5-dienes). This conversion is accomplished by catalytic hydrogenation of the starting compounds with a calculated amount of hydrogen, in order to hydrogenate only the double bond in the 5-position of the A -diene system. The so obtained enolethers of 3-keto-5a-steroids are identical to the products prepared by pyrolysis of the diacetals of 3-saturated ketones which compounds are characterized by having a double bond in the 2:3 position. The A -structure has been confirmed following many procedures and is till now the only known structure for the enolethers of 3-keto-5u-steroids (Fieser, Steroids, pp. 310-311).

It has now been found that carrying out the catalytic hydrogenation of the enolethers of M-S-ketosteroids in the presence of a catalytic amount of a basic substance, new enolethers of 3-keto-5a-steroids are obtained with a A -structure. Accordingly, the invention provides a process for the preparation of ethers of 3-hydroxy-A -5asteroids from the enolethers of the corresponding A -3- ketones by catalytic hydrogenation in the presence of a catalytic amount of a basic substance, such as an organic or inorganic base.

The process of the present invention can be generally applied to the enolethers of A -3-ketosteroids and 19-norsteroids of the androstane, pregnane and cholestane series, in order to obtain the corresponding ethers of 3-hydroxy- A -5a-steroids and 19-nor-steroids.

The new compounds of this invention may be represented by the following general formula:

where S completes the steroid nucleus, Y represents methyl or hydrogen and R represents a hydrocarbon radical selected from aliphatic hydrocarbon radicals, containing from one to ten carbon atoms, cycloaliphatic hydrocarbon radicals containing from four to seven carbon atoms, benzyl and aryl radicals.

Many of the new compounds of this invention possess useful biological properties, In particular, the compounds of the following formula:

CHiR

(where R is as defined above, R is hydrogen, a hydroxy group or an acyloxy group derived from a lower alkanoic acid containing 1-7 carbon atoms, R is hydrogen, a hy- RO i (where R represents an aliphatic hydrocarbon radical from five to ten carbon atoms, or a cycloaliphatic hydrocarbon radical from four to seven carbon atoms, Y is hydrogen or methyl and R represents a ketonic oxygen or a grouping in which X is hydrogen or the acyl residue of a lower alkanoic acid and R represents hydrogen or a lower hydrocarbon radical containing from one to three carbon atoms) possess antigonadrotopic and antihypophysary activity and are useful to induce a decrease of hypophysis hormonal secretion.

Further, the new ethers of 3-hydroxy-A -5u-steroids and l9-nor-steroids are useful intermediates for the preparation of 4-hydroxy-3-keto-5a-steroids.

The prior art discloses 4-hydroxy derivatives of A -3- keto-steroids and also discloses methods for preparing A 3-ketones hydroxylated at the 6-position (Journal Organic Chemistry 19, 1509; 1954, and 26, 974; 1 961), but no disclosure is known of the 4-hydroXy-3-keto-5a-steroids and no method has been heretofore developed for introducing a hydroxy group into the 4-position of saturated 3-ketosteroids.

According to the present invention, the 4-hydroXy-3- keto-Sa-steroids are now available by treating the ethers of 3-hydroxy-A -5u-steroids with a peracid. Therefore, the process of this invention comprises hydrogenating the enolethers of A -3-ketosteroids in the presence of a basic substance, isolating the resulting ethers of 3-hydroXy-A Soc-SICIOidS and converting said intermediates to 3-keto- 4-hydroxy-5a-saturated derivatives by a peracid treatment.

In applying practically the process of this invention the star-ting materials, enolethers of A -3-ketones, are reduced by catalytic hydrogenation with a calculated amount of hydrogen (a mole of hydrogen for each mole of the starting enolether), in the presence of a catalytic amount of a basic substance. Suitable basic substances are organic bases such as pyridine, piperi'dine, alkylamines, for instance, ethylamine, diethylamine, triethylamine, inorganic bases such as sodium, potassium or am monium hydroxide, organic or inorganic salts with basic properties such as, for example, sodium acetate or sodium phosphate.

The catalytic hydrogenation is usually carried out at room temperature (from +5 to +30 C.) in solution in an inert organic solvent and in the presence also of a suitable catalyst such as nickel, platinum and palladium supported on an inert material, for instance barium sulfate, calcium carbonate, alumina, diatomaceous earth and the like. Palladium on calcium carbonate is the preferred catalyst. Suitable solvents for the catalytic hydrogenations are alcohols, dioxan, tetrahydrofuran, benzene, hexane and dimethylformarm'de.

The hydrogenation step is over when a mole of hydrogen has been consumed for each mole of the 3-enolether reacted. The resulting ether of 3-hydroxy-A -5a-steroid is then isolated from .the reaction mixture by filtration, evaporation of the solvent to dryness and purification of the residue by crystallization. If desire-d, the solution containing the ether of the 3-hydroxy-A -5a-steroid can be directly employed for the further transformation.

The ethers of 3-hydroxy-A -5a-steroids and 19-norsteroids of the androstane, pregnane and cholestane series, are converted to the corresponding 4-hydroxy-3-keto- Sol-steroids by treatment with a peracid such as performic, peracetic, perbenzoic or monoperphthalic acid or with hydrogen peroxide. Although any ether can be used as intermediate in said conversion, it is preferred using a lower alkyl ether such as, for example, methyl or ethyl. The reaction is usually carried out in solution in an inert organic solvent and at a temperature between 0 and C. Suitable inert organic solvents are, for example, benzene, toluene, hexane, petroleum ether, methylene chloride or chloroform. Ethers, such as dioxan, tetrahydrofuran or diethyl ether can also be employed as solvents.

The compounds obtained at the end of the treatment are a mixture of the 4m and 4,8-isomers of the 4-hydroxy- 3-keto-5m-steroid and the mixture is separated into its components by chromatography or on fractional crystallization. The yield in 4-hydroXy-3-keto-5o-steroid is often higher than 80% of the theoretical amount.

The enolethers of A -3-ketosteroids used as starting mas ketone with an alkyl orthoformate or with the appropriate '30 terial for the process of this invention are generally well known. They can be prepared by treatment of the M-3- alcohol according to known procedures. The higher aliphatic and the cycloaliphatic enolethers may also be obtained from the corresponding ethyl enolether by treatment with the appropriate aliphatic or cycloaliphatic alcohol according to an exchange reaction as disclosed in the U.S. Patent No. 3,019,241.

The following examples serve to illustrate the methods not to be regarded as limiting the invention.

Example 1 0.2 g. of PdO supported on alumina (2% in Pd), suspended in 4 cc. of methanol, are treated with hydrogen to reduce the PdO to free palladium. Then a solution of 40 for the preparation of the new compounds but they are 1 g. :of 3-cyclopentyl enolether of testosterone in a mix- I ture of 10 cc. of tetrahydrofuran and 2 cc. of methanol, containing a drop (about 0.04 cc.) of pyridine, is added.

The reaction mixture is hydrogenated at room temperature and at atmospheric pressure until hydrogen is consumed in the ratio of one mole for each mole of the starting material. The catalyst is filtered ofr and the mixture is concentrated under vacuum. The residue, after crystallization from methanol consists of 3-cyclopentyl-i 127-129 C.;,

oxy-A -5a-androstene-17 8-01, Pt. [a] '=+11 (dioxan).

This new compound difiers from the isomeric 3-cyclopentyloxy-A -5a-androstene-17,8-01, described in the Example 1 of our copend'ing U.S. application Serial No.

124,385, filed on July 17, 1961, and noW U.S. Patent No.

3,118,917, by a lower value for the specific rotation.

The A -structure for the 3-cyclopentyloxy-A -5a-andrm= 4 Example 2 A solution of 1 g. of 3-cyclopentyloxy-A -5a-androstene-17 8-ol'in 20 cc. of anhydrous ether is treated with a 12 ,cc. of a 0.3 N solution of monoperphthalic acid in 1 1 ether.

at 10 C. .Afterwashing the reaction mixture with aque- 1 ous sodium carbonate :and with water, the ethereal SOIIP. I tion;is dried over sodium sulfate and .thenconcentrated i The reaction mixture is :leftstanding over night under vacuum. The residue consists of a mixture of 40:

and 418-isomers of ;4,17B-dihydroxyr5u-androstane-3-one.-

By repeated irecrystallizations from ether-hexanethere are separated 4a and 4B-isomers. stane-4a,17fi-diol-3-one shows melting point 193-195" C.; [a] =+51. (chloroform).

Example. 3

After reducing with hydrogen 0.2 g. of PdO on calcium,

carbonate suspended in 5 cc. of ethanol, 1 g. of 3-ethyl enolether of testosterone,v dissolved in a mixture of 10 cc. of tetrahydrofuran land 3 cc. of methanol is added to Example 4 1.5 g. of 3-ethyl enolether of testosterone acetate is dissolved in a solution of 12 cc; 'oftetrahydrofuran and 3 cc. of methanol. After adding a few drops of ethylamine, the reaction mixture is treated with hydrogen at room temperature, in the presence of-0.2 g.- of palladium on calcium carbonate to give 3-ethoxy-A-5u-androstene 17,8-01-acetate, M. Pt. 111-114 C.; [a] =+3 (dioxan 0.3%). Likewise starting from the corresponding 3- enolethers of testosterone acetate .the. following new' compounds are prepared; 3-methoxy-A -5a-androstene-17fi-o1-acetate, M. Pt. 117- 120 C.; [a] =+1.5 (dioxan 0.3% 3-cyclopentyloxy-A -5a-androstene-17fi-ol-acetate, M. Pt.

101-104 C.; [a] =+2.5 (dioxan 0.3%); 3-octyloxy-A -Sa=andnostene-l"Idol-acetate, Pt. 79-

C.; [a] I.5 (dioxan 0.3%) 1 g. of 3-ethoxy-A -5u-androstene-17,8-ol-acetate, dissolved in 20 cc. of anhydrous ether, is treated with 0.3.

Ns'olution ofmonoperphthalic acidin ether, accordingto the procedure of Example 2. Thereis obtained 700 mg.

of residue which, after repeated recrystallizations from ether-hexane, gives 5aean-dmstaner4a',17B-diol-3 one 17- :acetate, M. Pt.:191-'19,5 C.; [u]t "=9. (chloroform).

Example 5 10 -mg..of sodium hydroxide: previously dissolved in 10 cc. of methanol are added to a;solution of 5 g. .of cyclopentyl enolether of testosterone .propionate in 50 cc..of tetrahydrofuran. in the presence of .1 g.,of palladium on aluminatabout 2%) intmethanol solution, to give -3-cyclopentyloxy- A 5a-androstene-l7fl-ol propionate, M. Pt. 91.5-92.5 C.;

. By treating this compound With 0.2. Nsolution of peri acetic acid in tetrahydrofuran, therelis obtained the 40:

and 4,3-isomers of 5tz-anclrostane-4,17fl-diol-3-one .17-propionate.-

- Ex'ample6 By substituting an equivalent-quantity of 3-ethyl eno1-' ether of A -androstene-3,l7-dionein the: process of Exam-:

The pure Sol-andro- The obtainedmixture is hydrogenated pie 5, 3-ethoxy-A -5ot-androstene-17-one M. Pt. 128-131 C.; [a] =+67 (dioxan).

is obtained,

Following the procedure of Example 5, the 3-ethoxy- A -5m-androstene-17-one, is converted to 5uaandrostane- 4a and 4fi-ol-3,17-dione.

Example 7 Following the procedure described in Example 1, the 3-cyclopentyl enolether of progesterone is catalytically hydrogenated in the presence of disodium phosphate to obtain 3 cyelopentyloxy-M-5a-pregnen'e-20-on e, M. Pt. 8890.5 C.; [a] =+7S (dioxan 0.3%). In the same manner are prepared:

3-n-butyloxy-A -5a-pregnene-ZO-One;

3- (4-methyl) -pentyloxy-A3-5a-pregnene-20-one; 3-npentyloxy-A -5a-pregnene-2O-one; 3-n-heptyloxy-A -5a-pregnene-20-one; 3-cyc1ohexyloxy-A -5 a-pregnene-20-one; 3-nonyloxy-A -5u-pregnene-20-one; 3decyloxy-A -5a-pregnene-ZO-One and 3-benzyloxy-A -5a-pregnene-ZO-one.

By further treatment of the above obtained 3-cyclopen tyloXy-A -5oc-pregnene-20 one with monoperphitha-lic acid, there is obtained a mixture of 5a-pregnane-4a-ol-3, 20-dione and 5a-pregnane-4fl-ol-3,20-dione. The 4a and 4,6-isomers are separated by ,chromatography on neutral alumina.

Example 8 M 2 g. of 3-ethyl enolether of cholestenone are hydrogenated in the presence of triethylamine and palladium on alumina as catalyst, thus obtaining 3-ethoxy-A -cholestene, M. Pt. 64-67 C.; [a] =+25.5 (dioxan 0.3%). 7

Similarly, starting from the corresponding enolether, the 3-n-amyloxy, 3-cyclopentyloxy and 3-benzyloxy-A cholestene are prepared.

To a solution of 1 g. of 3-ethoxy-A -cholestene in benzene, there is added 12 cc. of a 0.5 N solution of perbenzoic acid. After standing overnight at room temperature, the precipitate is separated by filtration and re-- peatedly recrystallized from ether-hexane to give' 200 mg. of 5a-cholestane-4u-ol-3-one, M. Pt. 176-177 'C.; [a] =+15 (chloroform).

Example 9 Following'the procedure described in Example 1 and starting from the 3-ethyl enolether of 19-no.r-testosterone 17-acetate, 3-ethoxy-19-nor-A -5a-androstene-17p-ol-acetate is obtained, M. Pt. 9597 C;; [a] :+32 (dioxan 0.5%) and successively converted to 19-nor-5a-androstane-4u,l7/8-diol-3-one 17-acetate.

Example In the same manner are prepared:

3-cyelopentyloxy-A -5a-pregnene-17a-0l-20-0ne;

3-cyclopentyloxy-A -5oc-pregnene-17a,21-dio1-20-one;

3-cyclopentyloxy-A -5a-pregnene-17a,21-diol-1 1,20-dione;

3-cyclopentyloxy-A -5a-pregnene-1 lB,17a,21-triol-20 one;

3-cyclopentyloxy-A -5u-pregnene-17a,21-diol-11,20-dione diacetate;

3-cyclopentyloxy-A -5a-pregnene-17a,2l-diol-2O-one-diacetate.

Treatment of 3-cyclopentyloxy-17a-acetoxy-A -5a-pregnene-ZO-one', in ether solution with a 0.3 N solution of monoperphthalic acid as in Example 4, provides Soc-pregnane-4a,l7u-diol-3,20-dione l7-acetate.

Example 11 Example 12 A mixture of 5 g. of is'opropyl enolether of cortisol and 12 mg. of sodium phosphate in 20 cc. of ethanol is worked up as described 'in Example 7 lilO give 3-isopropoxy-A -5a-pregnene-1 1B,l7oc,2l-triol-20-one. This compound, treated with a solution of per benzoic acid as in Example 8, gives] 5a-pregnane-4a,1lfl,17ot,21-tetrol-3,20- dione.

Example 13 2.5 -g. of 3-.butyl enolether of 17at-methyl-19-nortestosterone dissolved in 20 cc. of tetrahydrofur'an are hydrogenated in the presence of pyridine, as in Example 1,

to obtain 3-butyloxy-17a-methyl-l9-nor-A -5u-androstene-.

l7fi-ol. This compound treated with a solution of monoperphthalic acid atroorn temperature, gives 17OL-II1Cthyl- 19-nor-5a-androstane-4a,l7p-diol-3-one.

Analogously, 3-cyclohexyl enolether of 17u-methy119- nortestosterone is hydrogenated under. basic conditions to give 3 cyclohexyloxy 17u-methyl-19-nor-A -5wandrostene-l75-ol and converted'by treatment with monoperphthalic acid to 17a-methyl-19-nor-5a-androstane-4a,17,8- dio1-3-one.

Example 14 Substituting a stoichiometrically equivalent amount of 3-methyl enolether of 17u-rnethylestosterone for the 3-buty-l enolether of l7a-methyl-19-nortestosterone in the above example, there is obtained'3- meth0xy-17a-methyl- A 5u-androstene-17fi-ol.

Analogously, 3-(2'-ethyl)-butyloxy-17a-methyl-A -5uandrostene-l7fl-ol and 3-phenoxy-17a-methyl-A -5a-androstene-l7B-ol are obtained.

3-methoxy-17a-methyl-A -5a-androstene-17,8-01 (2 g.) is then treated with 0.2 N solution of performic acid in 20 cc. of anhydrous tetra-hydrofuran to give a mixture of 4a and 4B-isomers of 17a-methyl-5a-androstane-4,17 8- diol-3-one from which the 4a-isomer is separated by recrystallization of the mixture from ether-hexane.

Example 15 5 g. of S-cyolohexyl enolether of testosterone formate are hydrogenated catalytically in the presence of triethylamine as in Example 8, to form 3-cyclohexyloxy-A -5a- 7 androstene-17B-ol 17-formate, which by .treatment'wit-h monoperphthalic acid is converted into 5a-androstane-4a, 17 8-diol-3-one 17-f0rmate.

Example 16 7 Substituting a stoichiometrically equivalent amount of cyclohexyl enolether of testosterone oenanthate for the;

cyclohexyl enolether of testosterone formate in the above example, there is obtained 3-cyclohexyloxy-A -Soc-andro-c stene 17fi-ol-oenanthate. In the same manner, 3-cyc'lobutyloxy-A -Su-androStene- 17B-ol-oenanthate and 3-cycloheptyloxy-A -5a-androstene-. l

17 8-ol-oenanthate' are prepared. 3-cyclohexy1oxy-A -5aandrostene-l7fi-ol-oenanthate obtained as above, is treated with monoperphthalic acid as in Example 2, to give 5aandrostane-4a, 17fi-diol-3-one 17-oenanthate.

Example 17 5g. of 3-methy1 enolether of ll-keto-progesterone (obtained by treating ll-keto-progesterone with methyl orthoformate) are hydrogenated catalytically in the presence of pyridine, following the procedure set forth in Example 1, to give 3-methoxy-M-5a-pregnene-11,20-dione." This,

compound (2 g.) is then treated with monoperphthalic acid in benzene solution and thus converted to 4a and 413-- hydroxy isomers of 5u-pregnane-4-ol-3,11,20-trione.

Example 18 By operating as in Example 17 and substituting a stoichiometrically equivalent amount of 3-ethyl enolether of 19-nor-progesterone for the 3-met'hyl' enolether of 11- keto-progesterone, there is obtained 3-ethoxy-19-nor-A Saregnene-ZO-One. This compound, treated with mono-- perphthalic acid, gives and 4fl-hydroxy-19-nor-5a-preg-u name-3,20-dione.

Example 19 5 g. .of 3-n-hexyl enolether of cortisone 21-oenanthate are hydrogenated catalytically in the presence of sodiumr acetate, to form 3-n-hexyloxyc-A -5 ot-pregnene-17a,21-diol- 11,20-dione 21 oenanthate. This compound, treated with i monoperphthalic acid as in Example 2, gives Soc-pregnanc- 4a,17u,21-triol-3,11,20-trione ZI-oenanthate.

What we claim is:

1. A process for preparing ethers of 3-hydroxy-A -5asteroids of the formula: 1

where S completes the steroid molecule, Y is a member selected from the group consisting of hydrogen and methyl and R represents a hydrocarbon radical selected, from the group consisting of alkyl of from one to ten carbon atoms, cycloalkyl of from four to seven carbon atoms, benzyl and phenyl which comprises catalytically hydrogenating the corresponding enolethers of A -3- ketosteroids with a mole of hydrogen for each mole of the starting enolether in the presence of a catalytic amount of a basic substance.

2. A process as claimed in claim 1, in which said basic substance is selected from the group consisting of pyridine,

piperidine, an alkylamine, sodium ,hydroxide, potassium hydroxide and ammonium hydroxide.

8" 1 r 3. The process of claim 1, in which the ethersof 3- hYdroxy-ALSd-steroids are further reacted: and treated with an agent'selected from the group ;consisting. of an organic peracid and hydrogen peroxide to giveathe corresponding 4-hydroxy-3-keto-5a-steroids .as a mixture of 40a and 4,8-isorners.

4. The process of claim 3 in which said mixture of 40a and 4fi-isomers is separated into its individual jcomponents.

5. Ethers of 3-hydroxy-A -5a-steroidsi shaving the formulaic CllHzR i, H3O 53 R3 7 l Q IRO- I where R represents a hydrocarbon radical selected from the group consisting of alkyl of from five to ten carbon atoms and cycloalkyl of from four to seven carbon atoms,

Y isIa member selected from the group consisting of hydrogen and methyl and R is a member selected from the groupconsisting of oxygen and the grouping OX,v

s in which X is a member selected from the group consisting of hydrogen and lower alkanoyl and R is a member selected from the group consisting of hydrogen and alkyl of from 01165110 three. carbon atoms.

7. 3-cyc1opentyloxy A3 5a-androstene-175-01. 8. 3-cyc1opentyloxy-A r5aaandrostene- 17 8-01 propionate.

References Cited by the Examiner UNITED STATES PATENTS 3/1963 Caglioti et al.i c260239.55 1/1964 Ercoli et a1. ,260397-.5

LEWIS GQTTS, Primary Examiner. 

5. ETHERS OF 3-HYDROXY-$3-5A-STEROIDS HAVING THE FORMULA 